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Induced Derangement in Bone Mineral Density in Patients With www.nature.com/scientificreports OPEN Identifcation of a key gene module associated with glucocorticoid- induced derangement in bone mineral density in patients with asthma Suh-Young Lee1, Ha-Kyeong Won1, Byung-Keun Kim 3, Sae-Hoon Kim4, Yoon-Seok Chang4, Sang-Heon Cho1,2, H. William Kelly5, Kelan G. Tantisira6,7 & Heung-Woo Park1,2,6* Derangement in bone mineral density (BMD) caused by glucocorticoid is well-known. The present study aimed to fnd key biological pathways associated with low BMD after glucocorticoid treatment in asthmatics using gene expression profles of peripheral blood cells. We utilized immortalized B cells (IBCs) from 32 childhood asthmatics after multiple oral glucocorticoid bursts and peripheral blood mononuclear cells (PBMCs) from 17 adult asthmatics after a long-term use of oral glucocorticoid. We searched co-expressed gene modules signifcantly related with the BMD Z score in childhood asthmatics and tested if these gene modules were preserved and signifcantly associated with the BMD Z score in adult asthmatics as well. We identifed a gene module composed of 199 genes signifcantly associated with low BMD in both childhood and adult asthmatics. The structure of this module was preserved across gene expression profles. We found that the cellular metabolic pathway was signifcantly enriched in this module. Among 18 hub genes in this module, we postulated that 2 genes, CREBBP and EP300, contributed to low BMD following a literature review. A novel biologic pathway identifed in this study highlighted a gene module and several genes as playing possible roles in the pathogenesis of glucocorticoid- induced derangement in BMD. Derangement in bone mineral density (BMD) caused by glucocorticoids is well-known. Glucocorticoid treat- ment is the most common cause of secondary osteoporosis1 and can induce a dosage-dependent reduction in bone mineral accretion in childhood asthmatics2. We previously reported that polymorphisms located in CRHR1, TBCD and RAPGEF5 were associated with low BMD in childhood asthmatics afer a long-term treatment of glu- cocorticoids3–5. However, so far, there has been no comprehensive study to elucidate biologic mechanisms under- lying glucocorticoid-induced derangement in BMD in asthmatics who are frequently treated by glucocorticoid. A network based analysis is an emerging and promising approach and provides new insights into BMD genet- ics by grouping genes into modules which are enriched for particular biological processes6,7. Te present study aimed to fnd key biological pathways associated with low BMD afer glucocorticoid treatment in patients with asthma using weighted gene co-expression network analysis (WGCNA). For this purpose, we used gene expression profles of immortalized B cells (IBCs) from childhood asthmatics afer multiple oral glucocorticoid bursts and those of peripheral blood mononuclear cells (PBMCs) from adult asthmatics afer a long-term use of oral glucocorticoids. Peripheral blood is an easily accessible tissue, although 1Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. 2Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea. 3Department of Internal Medicine, Korea University Medical Center Anam Hospital, Seoul, Republic of Korea. 4Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea. 5Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. 6The Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 7Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA. *email: [email protected] SCIENTIFIC REPORTS | (2019) 9:20133 | https://doi.org/10.1038/s41598-019-56656-9 1 www.nature.com/scientificreports/ www.nature.com/scientificreports Childhood asthmatics† Adult asthmatics‡ (n = 32) (n = 17) Gender, male (%) 23 (71.9) 6 (35.3) Age, year 8.63 (1.93) 60.11 (11.71) Smoking, yes (%) Not applicable 3 (17.65) Body mass index, kg/m2 17.71 (3.21) 23.72 (5.18) Vitamin D, ng/mL 31.81 (9.97) 14.71 (7.72) Tanner stage (%) I/II/III/IV/V 24 (75.0)/6 (18.8)/1(3.1)/1 (3.1) Not applicable Baseline BMD Z-score −0.10 (2.23) Not available Ethnicity (%) Non-Hispanic white 32 (100) 0 Asian 0 17 (100) Cumulative dose of PD, mg 1188.40 (608.05) 3130.53 (1552.09) Final BMD Z-score −0.29 (0.81) −0.97 (1.37) Table 1. Characteristics of subjects enrolled. Data indicate mean (Standard deviation); BMD, Bone mineral density; PD, Prednisone; †Characteristics measured at enrollment of the CAMP study except cumulative dose of prednisone and the fnal BMD Z-score; ‡Characteristics measured at enrollment of the present study. Figure 1. Co-expression modules identifed in gene expression profles of Sham-treated immortalized B cells from childhood asthmatics. Top panel shows a dendrogram of 5,000 genes. Bottom panel shows colors corresponding to the cluster membership labels for each gene. it is not directly involved in bone biology. However, it was suggested that molecular profling of peripheral blood might refect physiological and pathological events occurring in diferent tissues of the body8. Moreover, recent reports showed that PBMCs could be used to assess glucocorticoid sensitivity or efcacy of osteoporosis treat- ment9,10. Taken together, we may use gene expression profles of peripheral blood cells for the purpose of search- ing what biologic pathways are related to glucocorticoid-induced derangement in BMD. Results A total of 32 childhood asthmatics whose IBCs and BMD profles were available and 17 adult asthmatics enrolled (Table 1). Applying WGCNA to the 5,000 genes expressed in Sham-treated IBCs, we could identify 10 modules with various sizes ranging from 125 genes in the purple module to 1,372 genes in the turquoise module (Fig. 1). To emphasize the impact of strong correlations over weak ones in the network construction, we chose an empir- ical sof threshold of 6, representing a strong model ft for scale-free topology (R2 > 0.8, Figure S1). A total of 63 genes could not be assigned to a module as a membership gene, and were grouped into the grey module which was not considered for further analysis. Eigengene values of two modules (blue and magenta modules) showed signifcant associations with the BMD Z score in multivariate linear regression analysis. Eigengene value of the blue module consisted of 794 genes was negatively associated with the BMD Z score (P = 0.00294), whereas that of the magenta module containing 199 genes showed a positive association (P = 0.000758) (Fig. 2 and Figure S2). To assess the reproducibility and generalizability, we tested if our results were replicated in other gene expres- sion profles from adult asthmatics (Sham-treated PBMCs). Replication analysis was done in two ways: preser- vation of module (the consistency of network module structure across gene expression profles) and association with the target phenotype (association between corresponding eigengene values and the BMD Z score). Among 10 modules identifed in the discovery cohort, three modules (turquoise, magenta and purple modules) were signifcantly preserved in the replication cohort (Fig. 3). Module preservation statistics and P values are presented SCIENTIFIC REPORTS | (2019) 9:20133 | https://doi.org/10.1038/s41598-019-56656-9 2 www.nature.com/scientificreports/ www.nature.com/scientificreports Figure 2. Associations between eigengene values of the bone mineral density Z score-associated common module and the bone mineral density Z score. (A) Childhood asthmatics. (B) Adult asthmatics. Both P values were adjusted by covariates. Figure 3. Preservation of modules identifed in gene expression profles of Sham-treated immortalized B cells from childhood asthmatics in gene expression profles of Sham-treated peripheral mononuclear cell from adult asthmatics. Te frst (top) panel shows a heatmap of pair-wise correlations among the genes comprising the turquoise, magenta, and purple modules. Te second panel shows a heatmap of the edge weights (connections) among the genes comprising the three modules. Te third panel shows the distribution of scaled weight degrees (relative connectedness) among the genes comprising the three modules. Te fourth panel shows the distribution of node contributions (correlation to module eigengene) among the genes comprising the three modules. Genes are ordered from lef to right based on their weighted degree in the discovery cohort, so as to highlight the consistency of the network properties in the replication cohort. in Table S1. Multivariate linear regression analysis showed that eigengene value of the magenta module was signif- icantly associated with the BMD Z score in the replication cohort (P = 0.0104) (Fig. 2). Based on these fndings, we defned the magenta module identifed in gene expression profles from childhood asthmatics as the BMD Z score-associated common module. Among 199 membership genes in the BMD Z score-associated common module, 18 genes (ARMC5, ATP2A2, CCNK, CREBBP, EP300, EP400, GTF3C1, IPO13, MTF1, NOL8, NUP188, PCF11, RFX5, SDAD1, SETD1A, SLC25A22, UBAP2L, WDR59) were taken as hub genes due to their high con- nectivity and association with the BMD Z score (Figure S3 and Table S2). To evaluate in vitro perturbation of modules identifed in gene expressions of Sham-treated IBCs by Dex, we measured changes of the module structure between Sham- and Dex-treated IBCs. Among the 10 modules, only the magenta module identifed in Sham-treated IBCs was not preserved in Dex-treated IBCs (a maximal SCIENTIFIC REPORTS | (2019) 9:20133 | https://doi.org/10.1038/s41598-019-56656-9 3 www.nature.com/scientificreports/ www.nature.com/scientificreports Figure 4. Co-expression network of hub genes of the bone mineral density Z score-associated common module. (A) Sham-treated IBCs from childhood asthmatics. (B) Dex-treated IBCs from childhood asthmatics. For clarity, only the edges corresponding to the Pearson correlation coefcient >0.8 were shown.
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